New Molecular Mechanism Underlying Myc-Mediated Cytochrome P450 2E1 Upregulation in Apoptosis and Energy Metabolism in the Myocardium
New Molecular Mechanism Underlying Myc-Mediated Cytochrome P450 2E1 Upregulation in Apoptosis and Energy Metabolism in the Myocardium
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Myc 介导的细胞色素 P450 2E1 上调心肌细胞凋亡和能量代谢的新分子机制
DOI：
10.1161/jaha.118.009871
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发表时间：
2019-01-08
影响因子：
5.4
通讯作者：
Lu, Dan
中科院分区：
文献类型：
--
作者：
Guan, Feifei;Yang, Xinlan;Lu, Dan
背景-经典研究表明，细胞色素P450 2 E1（CYP 2 E1）在外源性物质的代谢中起着关键作用，并最终参与组织损伤。CYP 2 E1在多种疾病的病理生理学发展中上调，然而，CYP 2 E1上调的机制，特别是在心脏病中，仍然是难以捉摸的。方法和结果-我们发现，CYP 2 E1水平在肥厚型心肌病患者的心脏组织中升高;和HL-1心肌细胞。我们通过生物信息学分析、荧光素酶活性和染色质免疫沉淀确定Myc与CYP 2 E1启动子结合并激活其转录，并通过信号转导分析确定Myc表达受细胞外信号调节激酶1/2和磷脂酰肌醇3激酶/蛋白激酶B途径的调节。此外，氧化应激和细胞凋亡的水平逐渐恶化，随着年龄的增长，在转基因小鼠过度表达CYP 2 E1，这是显着抑制与CYP 2 E1 knockdown. Conclusions，我们的研究结果表明，CYP 2 E1可能是一个传感器的各种病理生理因素和状态的心肌。上调的CYP 2 E1在心脏中具有多种病理生理作用，包括增加氧化应激和细胞凋亡以及能量供应以满足某些疾病状态下心脏的能量需求。因此，我们的发现为靶向Myc和CYP 2 E1的心脏病治疗策略提供了基础。
Background-Canonical studies indicate that cytochrome P450 2E1 (CYP2E1) plays a critical role in the metabolism of xenobiotics and ultimately participates in tissue damage. CYP2E1 upregulates in the pathophysiological development of multiple diseases; however, the mechanism of CYP2E1 upregulation, particularly in heart disease, remains elusive.Methods and Results-We found that the level of CYP2E1 increased in heart tissues from patients with hypertrophic cardiomyopathy; multiple mouse models of heart diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and myocardial ischemia; and HL-1 myocytes under stress. We determined that Myc bound to the CYP2E1 promoter and activated its transcription by bioinformatics analysis, luciferase activity, and chromatin immunoprecipitation, and Myc expression was modulated by extracellular signal-regulated kinases 1/2 and phosphatidylinositol 3 kinase/protein kinase B pathways under stress or injury in myocardium by signal transduction analysis. In addition, the level of oxidative stress and apoptosis gradually worsened with age in transgenic mice over-expressing CYP2E1, which was significantly inhibited with CYP2E1 knockdown.Conclusions-Our results demonstrated that CYP2E1 is likely a sensor of diverse pathophysiological factors and states in the myocardium. Upregulated CYP2E1 has multiple pathophysiological roles in the heart, including increased oxidative stress and apoptosis as well as energy supply to meet the energy demand of the heart in certain disease states. Our discovery thus provides a basis for a therapeutic strategy for heart diseases targeting Myc and CYP2E1.